Viral Carrier Status is Instilled by Viral Regulatory Particles

Viral Carrier Status is Instilled by Viral Regulatory Particles

Rand Wheatland

The Endocrine Research Project, 574 Sims Rd., Santa Cruz, CA 95060, USA
E-mail: rwheatla@query.com

Originally published in the journal Medical Hypotheses, 2010;74(4):688-91. But this HTML version has color figures.

Summary Human viral carriers are important agents in the periodic resurgence of many pathogens. Instillation of virus in human carriers explains several of the unusual epidemiological features of viral epidemics, such as where viruses linger between epidemics and how epidemics can arise without an apparent source. By inactivating itself, a virus can easily reside in a host for months or years without being noticed by the immune system, enabling the virus to be dispersed inconspicuously in the future and into new regions. When this silent activity of human carriers is appreciated, it is easier to understand the dynamics of viral epidemics, such as the explosive appearance of influenza epidemics.

During viral illnesses, virus in infected cells is put into a latent state by regulatory sequences delivered by particles produced by other virus-infected cells. These regulatory particles are similar to the virus's virion but contain specific subsets of the viral genome and cannot replicate in cells that are not infected by the complete viral genome. Regulatory particles have previously been referred to as defective interfering particles, noninfective viruses, inactive viruses, incomplete viruses, satellite viruses, and defective viruses.

There are still many unanswered questions regarding viral carrier creation and the role human carriers play in the pathology and epidemiology of viral diseases. Some of these questions are presented and discussed in relation to regulatory particles, possible investigations and how carrier status may affect the health of the carrier.

Viral regulatory particles limit the extent of viral infections and shift the active infection to a latent infection. Just as multicellular creatures use hormones as chemical messengers to coordinate cellular functions, viruses utilize regulatory particles to coordinate viral modes among infected cells within a host. Many viruses depend on these particles for their continued existence. If we wish to comprehend and effectively treat viral infections, we must secure a thorough understanding of viral regulatory particles.

Human viral carriers are important agents in the periodic resurgence of many pathogens (1). A viral carrier is a host who is persistently infected by a virus that exhibits little or no activity, except when the virus blooms to disseminate viral seeds. This condition is also described as a latent infection.

Instillation of virus in human carriers explains several of the unusual epidemiological features of viral epidemics, such as where viruses linger between epidemics and how epidemics can arise without an apparent source. Influenza epidemics have been well studied and are a good example of these mysteries. Influenza A and B are seasonally epidemic, generally appearing during the cold season, or the rainy season in the tropics (2). Few human influenza infections are observed during the interval between epidemics. When influenza does appear, it spreads quickly over large regions but may slowly diffuse over relatively small distances (3). Widespread latent infection of human carriers allows influenza to be widely and simultaneously disseminated when awakened by an environmental trigger. No other mechanism satisfactorily explains the explosive appearance of an influenza epidemic after a prolonged absence.

By inactivating itself, a virus can easily reside in a host for months or years without being noticed by the immune system, enabling the virus to be dispersed inconspicuously in the future and into new regions. Although their activity is not readily apparent, the source of many viral epidemics can be attributed to asymptomatic human carriers who are occasionally infectious. For example, for hundreds of years, ship's surgeons have noted that influenza epidemics have begun on ships that have been at sea for weeks with the entire crew being healthy until the epidemic began (4). Influenza epidemics have also been reported that began in isolated communities soon after a ship (5) or a plane (6) arrived even though no one on board appeared to be suffering from the disease before or during the epidemic. Clearly, human viral carriers were the source of these epidemics.

Influenza epidemics tend to be dominated by a single strain. A wave of influenza infections by a new, nondominant strain of virus is called a herald wave (7,8). Herald waves can happen at any time but are most noticeable at the end of the influenza season, when physicians still have a high suspicion for an influenza diagnosis and the new strain represents a large proportion of influenza cases. An excellent example of a herald wave is the novel strain of H1N1 influenza virus that circulated widely from March to July, 2009 (9). The influenza surveillance data in Fig. 1 shows a similar H1N1 herald wave that occurred in Japan from March to July, 1986. During a herald wave, carriers are seeded with the new influenza strain, positioning the virus so it can initiate an epidemic. If the herald wave is able to infect many hosts, it is a sign that the dominant strain's influence is waning and that the herald strain will probably supplant the dominant strain in the next epidemic. The herald wave only makes sense when the role of human viral carriers in starting influenza epidemics is appreciated.

Fig. 1. Influenza surveillance, Japan (1985-1987). Data represents the total number of isolates per month that were identified by strain as reported to the National Institute of Health in Japan. [Adapted from the Annual Report of National Epidemiological Surveillance of Vaccine-Preventable Diseases, 1992, Fig. 4 and Nakajima et al. (10), Fig. 1]

Periodic infectious activity is an efficient alternative to perpetual viral transmission. This strategy conserves and allows time for renewal of the pool of susceptible hosts (11). In addition, a virus gains much more mobility by silently residing in its host. If a virus could only spread from an ill host within a short period after infecting the host, the distance it could travel from the point of infection would be limited. However, if a virus establishes a latent infection, when it awakens later to spread its virions, it may have traveled thousands of miles. Since the virus is not confined to a single community, its long-term survival chances are vastly improved.

Viral Carrier Creation

How are human viral carriers created during viral illnesses? Virus in infected cells is put into a latent state by regulatory sequences delivered by particles produced by other virus-infected cells. These regulatory particles are similar to the virus's virion but contain specific subsets of the viral genome and cannot replicate in cells that are not infected by the complete viral genome (12,13). When the complete virus and its regulatory sequence are coresident in a cell, the virus makes fewer virions and more regulatory particles. Essentially, the virus goes to sleep while communicating to other virally infected cells to do the same. The virus uses this method to coordinate a change in modes after reaching an adequate infection level.

A virus can be quite successful if it can latently infect carriers who will spread the virus to begin new epidemics and possibly introduce the virus to new areas when their host travels. To accomplish this, the virus must avoid killing its host and delay becoming latent until enough cells are infected so that, when awakened, it will be able to produce abundant viral shedding before being stopped by the immune system. Viruses do this by disseminating regulatory particles. Regulatory particles have no effect on virion production unless their regulatory sequences are in cells that are infected with the complete virus. Therefore, viral infections do not create many latently infected cells until virus-infected cells and regulatory sequence-containing cells have each reached a density threshold. As more infected cells contain the regulatory sequence, the number of regulatory particles increases substantially, which should bring the infection to an abrupt end and also keep the virus from killing its host. Fig. 2 illustrates the transition from an active infection to a latent infection on a local scale by a series of snapshots of the infectious state of the same cells over time.

Fig. 2. The dynamics of viral regulatory particles

During the 1940s and 1950s, it was noticed that virus was difficult to grow when the culture was started with concentrated inocula that had come from extended incubations (14,15). Also, after several undiluted passages in cell or tissue cultures, the harvested fluid lost its infectability in hosts (14,15). Researchers isolated the particles responsible for the interference with the culture growth and described their properties: their proteins and antigenicity were similar to virions and the particles inhibited the propagation of the virus (13,16). Later, these particles were inappropriately named defective interfering particles (12). They should properly be called regulatory particles because they are not defective and they perform more than an interfering function. These particles have also been referred to as noninfective viruses, inactive viruses, incomplete viruses, satellite viruses, and defective viruses. Regulatory particles are not viruses or viral seeds. They are viral tools. They can implant themselves in a cell but they cannot reproduce without viral assistance. Therefore, they cannot be said to infect cells.

Although the regulatory function of regulatory particles was discovered over forty years ago, the importance of these particles in the pathogenesis and epidemiology of viral diseases has not been recognized. There are many fundamental questions regarding viral carriers and viral regulatory particles that need to be investigated. Several of these questions vital to understanding viral infections are:

Does every individual ill from a viral infection become a carrier?

If a virus produces regulatory particles, which most viruses appear to produce (16-19), do a few cells always become latently infected during a viral illness? How many latently infected cells are required to become an effective viral carrier? If becoming an effective carrier is not a certainty after surviving a viral illness, naturally infected animals can be studied to investigate whether there are factors that support the instillation of carrier status, factors such as season, nutrition, age, gender, crowding, and illness severity. For instance, do these factors alter the rate of spontaneous generation of viral regulatory particles?

Do latently infected carriers ever clear the virus?

Some viral carriers may clear their virus upon the first awakening or bloom of the virus. Other carriers may carry and occasionally spread the virus over their remaining lifetime. Does the duration of the carrier state depend more on a person's immune system or on the particular virus? If the carrier status for a virus is not permanent, can the virus be cleared while it is latent, as it assumes a very low profile, or must the host wait for the virus to bloom before the host's immune system can act? Upon awakening, how well does the immune system detect the virus and how long does the carrier shed virions?

What fraction of the population are carriers of each type of virus?

To understand the epidemiology of viruses it would be helpful to know the prevalence of carriers for each virus type, by age. Since carrier status may influence mortality, this bias in estimating prevalence can be minimized by performing a survey of people that have died after accidents. PCR analysis of samples should be able to identify viral carriers and determine which organ, gland or cell type is the viral reservoir. The study's utility can be increased by searching for many different viruses in each sample (20).

What triggers a latent virus to awaken?

Some environmental factors that have been proposed as triggers for carrier-provoked epidemics are day length, changes in temperature or humidity and stress, resulting from situations such as crowding or travel. Records of ships at sea that have reported epidemics starting on board at the same time as epidemics arose on the coast that they were passing (4) is evidence that local meteorological conditions can stimulate latent infections to awaken.

Most environmental triggers must awaken latently infected cells via normal physiochemical processes. A latently infected lung epithelial cell does not respond directly to the length of the day, the cell only notices changes in its local chemical milieu. Therefore, to understand how a latent virus blooms, its environmental trigger and associated cellular activator should be identified.

Since cells in vitro can be latently infected using a mixture of virions and regulatory particles (21-23), it is relatively simple to conduct experiments into the chemical factors necessary for interrupting latency. Latently infected cells can be challenged by a number of different chemical concentrations, combinations and concentration transitions to determine which stimulus will restore the latently infected cell's virion production. Obvious environmental factors to test are: length of day (using vitamins and hormones that demonstrate seasonal differences, such as vitamin D and melatonin) and stress (via stress hormones, such as cortisol and ACTH).

Does the awakening of a latent virus affect the carrier?

When a carrier's latent viral infection awakens and the virus is being spread, the carrier does not usually appear to be sick. Although the carriers are said to be asymptomatic, do they still suffer from some symptoms that are not notable because the symptoms are mild, common, alterations of mood or are of a short duration? Symptoms such as being sleepy, fatigued, depressed or irritable may occur when a carrier's virus is blooming but are ignored because, normally, these symptoms are not complained about or clinically acknowledged until the symptom becomes chronic and sufficiently severe. When a latent infection blooms, to maximize its transmission potential, it needs its host to associate with as many contacts as possible. Since a person with severe symptoms will often isolate themselves and people tend to avoid a sick person, the infection will encounter many more possible victims if its host does not appear to be ill. Therefore, the awakening of a latent infection may have some negative effects on its host's well-being but if the infection refrains from inducing obvious signs of illness, it can spread to numerous casual contacts.

The blooming of a latent viral infection may be responsible for the condition known as Seasonal Affective Disorder (SAD). SAD is major depression that recurs seasonally. In the most common type of SAD (winter type) patients experience symptoms of atypical depression during the fall and winter, including excessive sleepiness, increased appetite, carbohydrate craving and weight gain, and attain full remission during the spring and summer (24,25). For many winter type SAD patients, daily exposure to bright artificial light is an effective treatment for avoiding or significantly decreasing depressive symptoms during the fall and winter (24,25). Does this imply that the symptoms of SAD can be avoided if the latent infection's environmental trigger is nullified?

Which is most important for the normal termination of a viral infection, viral regulatory particles or the immune system?

To a sophisticated, well-adapted virus, the immune system as opposition may just be a nuisance. In this case, does the virus control the peak level of infection, becoming latent when it reaches its programmed threshold? By limiting its spread within its host, a virus protects the host from superinfection, ensuring the survival of its carrier.

In addition to the self-regulation mediated by regulatory particles during a viral illness, is carrier status partially responsible for immunity following the illness? Upon reinfection with a virus that responds to the same regulatory particles, the virus can hardly reproduce in such a host since many of the virus's target cells are already implanted with regulatory sequences. Similarly, are the regulatory particles in live vaccines, such as the measles (26), oral polio (27) and intranasal influenza vaccines, responsible for the vaccines' effectiveness? If regulatory particles play a role in resistance, is waning immunity due to decreasing levels of latently infected cells?

Since regulatory particles block the spread of virions within an infected host, can these particles be used therapeutically for terminating severe viral infections? If regulatory particles can be an effective therapy, this treatment should be used with caution. Creating an unnatural latent infection in a patient may cause serious problems later.

Conclusion

Conflicts of interest statement

None declared.

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